Brain cells neuroprotection induced by TNF-α and LRP5

Acute myocardial infarction (AMI) triggers a systemic inflammatory response that can lead to remote organ damage, including the brain. While the Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5)-mediated canonical WNT pathway is a known regulator of cell survival in peripheral tissues, its role in the brain post-MI is unknown.

Myocardial infarction was induced in Wt and Lrp5^-/- mice and infarct size and mortality were assessed. Serum from these mice was used to treat neuronal cultures. The specific effects of TNF-α were investigated in LRP5-silenced neurons and microglia, with analyses of apoptotic markers, LDH release and key signaling pathways (WNT/β-catenin and NF-κB).

Lrp5^-/- mice showed significantly higher mortality and larger infarcts and its serum increased the pro-apoptotic profile in differentiated SHSY5Y neurons. TNF-α exerted prosurvival effects in neurons and microglia through distinct mechanisms. In neurons, TNF-α protection was LRP5- and NF-κB-independent while in microglia, TNF-αinduced survival and Bcl₂ upregulation required both LRP5 and NF-κB signaling. The canonical WNT pathway was not involved.

LRP5 deficiency aggravates cardiac injury and is associated with increased neuronal susceptibility to inflammatory signals. In vitro, LRP5 selectively mediates TNF-α-dependent survival in microglia via NF-κB while neuronal responses to TNF-α occur through LRP5-independent pathways. These data reveal cell type-specific roles for LRP5 in the inflammatory response to MI and provide a foundation for further mechanistic investigation.